A pro-drug is, mostly, pharmacologically inactive compound of active parent drug molecule, which requires enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug. This fact of difference in transport and in-situ effect of characteristics for many drug molecules is the reason for the development of bio-reversible derivatization of drugs, i.e, prodrugs, which is a means by which a substantial improvement in overall efficacy of the parent drugs normally achieved.
In recent years, several types of bio-reversible derivatives have been exploited for proper utilization of drugs. This approach is mainly designed to enhance the solubility of poorly soluble drugs, or to improve the target drug delivery by avoiding hepatic first-pass metabolism or to enhance the stability.
Curcumin and its demethylated derivatives belongs to class of Curcuminoids and are polyphenolic pigments found in the spice turmeric and are responsible for the yellow color of turmeric. Curcuminoids are extracted from Curcuma longa belonging to the family Zingiberaccae and commonly known as Turmeric. Curcumin is the active ingredient of the Indian curry spice turmeric and it is one of three curcuminoids of turmeric, along with other two curcuminoids, demethoxycurcumin and bisdemethoxycurcumin. Curcumins are phenolic diarylheptanoids with characteristic yellow colored constituents of turmeric (Curcuma longa).
Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. Curcumin acts as an inhibitor for cyclo-oxygenase, 5-lipoxygenase and glutathione S-transferase. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450. All the above properties/activities of curcumin is very well documented in the literature.
In recent years, curcumin and its analogs, being natural products, have been the subject of alternative medicine for treatment of various neurodegenerative diseases, particularly, Alzheimers disease. Alzheimer's is a degenerative and terminal disease for which there is no known cure. Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.
Despite the beneficial effects of curcumin, the present inventors have noted that there are many bioavailability problems associated with the oral delivery of curcumin. Curcumin does not easily penetrate the human digestive tract and is subject to intestine-based metabolism and rejection, and hence less than 1% of oral curcumin enters the blood plasma. Moreover, the small amount of curcumin that enters the bloodstream is rapidly metabolized by the liver and kidney. Therefore, though curcumin is highly lipophilic (and so easily crosses the blood brain barrier), only very small amounts of orally administered curcumin are registered in the serum and in the brain tissue. Bioavailability studies reveals that ingesting up to 3.6 g of curcumin per day produced a plasma curcumin level in the range of only about 10 nM (Sharma, Clin. Cancer Res., 2004, Oct. 15, 10(20) 6847-54). Another study found that ingesting up to 6-8 g of curcumin per day produced a peak serum level in the range of about 0.51-1.77 μM. Moreover, it has been reported that high oral doses of curcumin in the range of 4,000-8,000 mg/day cause problems such as headache, rash and diarrhea, likely produced by metabolites of curcumin. Therefore, it appears that the above mentioned plasma curcumin concentrations (10 nM-1.77 μM) represent the practical available upper limit of oral dosing of curcumin. Yang, supra, concludes that higher >(5 μM) concentrations of curcumin are not likely to occur in the brain with oral dosing. In fact, Wang reports that injection of 30 mg/kg of curcumin results in a peak curcumin concentration in brain tissue of only about 0.15 ng/mg, which is about 0.40 uM.
It appears that, in the brain tissue concentration range about 1 uM, some but not all of the beneficial therapeutic qualities of curcumin are realized.
Curcumin and its demethylated derivatives have limited bioavailability while administered as oral dosage form due to hepatic first-pass metabolism. In the light of the above bioavailability problems, there exists a need for bioavailable curcumin.
It has been shown that the compounds of formula I fulfill the requirements of active prodrugs; which can effectively be used as oral therapeutic agents at lower doses.
The phrase “bioavailable curcumin” is used to refer the compounds of formula I, of the present invention and hence, wherever, the phrase “bio-available curcumin” appears in the specification, must be construed as a reference to compounds of formula I. Thus, the present invention provides bioavailable curcumin comprising an active constituent of curcumin i.e. bis-O-demethylcurcumin in an effective amount.